Genetic mutations play an important role in human aging and disease. By changing our genetic code, a mutation can disrupt the activity of a protein and permanently change the physiology of our cells. As a result, mutations can have a profound effect on human health. For instance, mutations in the germ line can result in congenital disorders, whereas somatic mutations contribute to cancer, muscle wasting and neuronal degeneration. An exciting new set of experiments now suggests that genetic mutations are not the only errors that contribute to human disease. In this research proposal, I will test the hypothesis that non-genetic mutations, i.e. mutations that occur during transcription and translation, also contribute to aging and age- related disease. To do this, I am developing highly sensitive technology that is capable of detecting these errors in vivo and I will use this tool to identify the parameters that modulate their error rates. Through genetic engineering I am also directly altering the error rate of transcription and translation to test whether this impacts celllar aging and age-related pathology. Finally, I will determine the molecular mechanisms by which non- genetic mutations impact cellular function, and identify the cellular pathways that are in place to prevent dysfunction. Together, these experiments may significantly deepen our understanding of aging and age-related pathology and help identify new targets for treatments or prevention strategies in the clinic. PUBLIC HEALTH RELEVANCE: Age-related diseases place an enormous strain on the medical and financial resources of Western society. Therefore, one of the most important challenges for modern medicine today will be to understand the molecular basis of the aging process. By understanding aging in greater detail, we may expose the driving force behind age-related diseases and thus discover new treatments or prevention strategies that are useful in the clinic. The primary goal of this research proposal is to understand how certain biological errors contribute to aging. These errors, which occur during protein expression, could play a role in various diseases, including Alzheimer and Parkinson disease. To achieve this goal, we will monitor these errors with highly sensitive techniques, record the lifespan of cells with increased error rates, and uncover the molecular underpinnings of our findings.